Plant Training on Aristopharma Ltd

Introduction

ARISTOPHARMA LTD. started through the formation of a proprietorship firm with the introduction of a few products in oral liquid & tablet form in 1986. In 1990 new manufacturing unit was commissioned at Shampur-Kadamtali with highly sophisticated and advanced facilities. In 1998 Production line was diversified with the addition of cream and ointment in the portfolio. In 2000 Company starts its international operation – Vietnam being the first country to export, and then export to Sri Lanka, Singapore, Myanmar, Hong Kong, Ukraine, UAE, and Mauritius etc country.

In 2002 Sterile Products Block is commissioned & Ophthalmic Products are introduced in the market. In 2009 Agreement is signed with APC, Australia to set up its 3rd plant at Gacha, Gazipur for Europe/American Market. Export starts to United Arab Emirates of Middle East and Nigeria of Africa. In 2010 Export starts to Pakistan. The new expansion building of factory starts operation with the facilities for inhalers, insulins, lyophilized injections, pre-filled injections, suppositories etc.

Plant of ARISTOPHARMA LTD.

Manufacturing facilities

The state-of-the-art-manufacturing facility of ARISTOPHARMA is located at Shampur-Kadamtali. The facility is planned and designed with fine tuned future orientation to meet the local as well as international demand both qualitatively & quantitatively.  Moreover, to meet the need of the market, company has set up a new plant beside its existing one. With 66000 sq. ft. floor area this new plant would help us to manufacture some new, high-tech products like inhalers, insulins, lyophilized injections, pre-filled injections, suppositories etc. The company is now working to build its 3rd plant at Gacha, Tongi for exporting its medicines to US & European market.

 The ophthalmic and parenteral products are manufactured in the newly commissioned sterile product block. This block, built on a turn-key basis by RETAN LTD. of Belgium brings in world class facilities for manufacturing sterile ophthalmic & parenteral dosage forms. This facility equipped with HEPA filter, laminar air flow and class 100 clean room is believed to be the most modern in the country. A good blend of Pharmacists, Chemists, Microbiologists & Engineers led by the Director, Production pay their relentless efforts to bring in the highest quality products.

Quality Assurance

In ARISTOPHARMA quality comes first, profit comes to its sequence & that is reflected in its motto: ‘Quality – the unit we count’. Strict quality control procedures are maintained at every step starting from sourcing of raw materials to dispatch of finished products. The latest WHO approved current Good Manufacturing Practices (cGMP) & current Good Laboratory Practices (cGLP) are followed in every step of operation. Written Standard Operating Procedures (SOPs) are maintained for every process. The total Quality Assurance activities are accomplished by two departments – Quality Compliance & Quality Control, which are comprised of competent Pharmacists, Chemists, Biochemists & Microbiologists.

Product Development

The motto of ARISTOPHARMA’s product development is to invent a healthier tomorrow. Their thrash is to support the valued customers with advanced & latest medicines at an affordable price. Every year around 20-30 new products are added to its portfolio, which is one of the many reasons that ARISTOPHARMA stands as one of the fastest growing pharmaceutical companies in the country.

Marketing

The theme of ARISTOPHARMA’s Marketing is to care for its customers and this responsibility doesn’t lie only on the shoulder of Marketing Department rather all the company’s departments work together to serve the customers’ interests and not only the external customers, but also the internal customers i.e. employees. The core marketing job is accomplished by six departments- Product Management, Sales, Distribution, Medical Services, Sales Training and Market Research.

Product management department (PMD)

Product Management Department lies in the center of all marketing activities. A dedicated team with solid professional background comprising Pharmacists, MBAs, Biochemists and Medical Graduates work in this department

 Sales Department

The sales department lies as an important part of marketing as they do the implementation part of all strategies. A large team of around 1200 highly skilled sales people work throughout the country to bring in success for the company.

Distribution Department

To make its quality products available at every corner of the country, ARISTOPHARMA has a strong distribution network comprising of 14 depots throughout the country. A dedicated team of around 450 people and a fleet of vehicles comprising delivery vans, three wheelers etc are engaged to distribute time of the products throughout the country.

Medical Services Department (MSD)

ARISTOPHARMA, believe that their responsibility does not end only in manufacturing and marketing quality medicines but also extends to the total improvement of the healthcare sector of the country. To do this, ARISTOPHARMA has established an independent Clinical Research and Medical Services Department (CRMSD) for the first time in Bangladesh. CRMSD comprised of medical graduates, assists in conducting Clinical Researches with their own medicines on their local people upon collaboration with different medical institutions. It also arranges seminars & symposia, publishes newsletters & articles and provides other professional services to the doctors.

Sales Training Department

They organize training for sales people. Training is organized both in the entry level as well as for existing people to keep them updated with product knowledge, selling skills etc.

Market Research Team (MRT)

The Market Research Team conducts prescription audit throughout the country to find out the prescription behavior of the doctors, which acts as the major input for formulating marketing strategies.

Export

With the aim to cope up with the challenges of globalization, ARISTOPHARMA started its export operation in 2000, Vietnam being the first destination. Today ARISTOPHARMA export to 12 countries of three continents namely Singapore, Sri Lanka, Myanmar, Vietnam, Bhutan, Pakistan, UAE & Macau of Asia; Ukraine of East Europe & Nigeria, Mauritius of Africa. Apart from usual tablet, capsule, syrup, suspension or cream/ointment, it also exports sophisticated ophthalmic dosage forms to Hong Kong and Myanmar. It is the 1st pharmaceutical company in Bangladesh to export to a developed country like Hong Kong & 2nd company to export to Singapore.

Now ARISTOPHARMA is moving aggressively to increase its market share in the operating countries as well as to invade new countries. Some other African countries & countries of Middle East are under active search.

Human resource

Skilled human resources are the key driving force of ARISTOPHARMA. Their success is based on attracting, developing & retaining talented & motivated human resource.

The employees of ARISTOPHARMA believe in collaborative spirit. They appreciate that working as a team multiplies the strength of the individuals involved as well as the impact of the results.

Skill acquisition & development of all staff is key to a company’s growth, we believe. In this regard, they are always on the look out to identify training needs of their employees in order to enable them to carry out the entrusted responsibilities. Training programs undertaken, not only address skills relating to the specialty of the individuals concerned, but also improving leadership skill.

The total no. of employees in ARISTOPHARMA is around 3000, and 60% of them are

 Pharmacists

 Chemists

 Biochemists

 Microbiologists

 Engineers

 CMAs

 CAs

 MBAs

 Doctors

 Others (Graduates)

 Training

The term training refers to the acquisition of knowledge, skills, and competencies as a result of the teaching of vocational or practical skills and knowledge that relate to specific useful competencies. During In Plant Training we know about how the pharmaceutical raw materials are processed from the dispensing of the materials to the finished products with maintaining its quality. In-plant training is a very important part in Pharmacy Education to achieve practical knowledge for every student.

Why In Plant Training is needed?

In Pharmaceutical Industry to build up the carrier as an industrial pharmacist every pharmacy graduate must have a practical experience on developing formulations, manufacturing, quality control and industrial management. It forms the core of apprenticeships and provides the backbone of content at institutes of technology. In addition to the basic training required for a trade, occupation or profession, observers of the labor-marketrecognize today the need to continue training beyond initial qualifications, to maintain, upgrade and update skills throughout working life. People within many professions and occupations may refer to this sort of training as professional development. To make the pharmacy graduates more competent and more experienced In-Plant training is essential.

On-the-job training takes place in a normal working situation, using the actual tools, equipment, documents or materials that trainees will use when fully trained. On-the-job training has a general reputation as most effective for vocational work.

Purpose of in-plant training

The purpose of in-plant training is given below-

• For the fulfillment of B.Pharm Degree.
• To achieve idea about the documentation and this is necessary for practicing GMP.
• To get ideas about the function of IPC (In Process Control) department.
• To achieve overall idea how cGMP standards are followed in a pharmaceutical industry.
• To correlate the theoretical knowledge with the practical knowledge.
• To get idea about the important machineries and equipments those are needed for the production and product analysis.
• To get ideas about the activities of QA (Quality Assurance) department.
• To get ideas about development department.

 Solid dosage forms are the most popular and convenient methods for drug delivery. Due to low production cost and easy manufacturing process manufacturer produces large amount of solid product. They can be produced in a non-sterile environment and the technology is well-known after more than 100 years of development. Since most pharmaceuticals are produced in solid dosage forms, it is important that the unit operations for their production be thoroughly understood. This course focuses on the fundamentals of each separate processing step (unit operation) required for the manufacture and packaging of tablets and capsules, the most common of solid dosage forms.

There are various types of solid dosage form resent in the world as tablets, capsules, pellets, powder for suspension etc. ARISTOPHARMA LTD. Bangladesh produces three types of solid dosage preparation. These preparations include tablets, capsules, and powder for suspension.

Manufacturing area of solid dosage form

In general terms, all unit operations required to get the unit into its finished form. Examples of these unit operations include blending, granulating, compressing, branding, and coating for tablets, as well as blending and filling for capsules. All solid dosage form manufacturing area are divided by

1. Manufacturing Area

• Tablet
  • Granulation Unit
  • Compression Unit
  • Coating Unit
• Capsule and Powder for suspension
  • Processing Unit
  • Encapsulation Unit
  • Filling Unit

1. Packaging Area

• Blistering Unit
• Packing Unit

 Capsule and Powder for suspension Area

 Manufacturing of Tablet

Tablet

Tablet is a pharmaceutical dosage form that may be defined as a solid dosage form containing drug substance with or without suitable excipients and prepared by compression or molding method. The excipients can include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet’s appearance. A tablet can be formulated to deliver an accurate dosage to a specific site; it is usually taken orally, but can be administered sublingually, buccally, rectally or intravaginally. Size of tablet to be swallowed range from a few millimeters to about a centimeter. Some tablets are in the shape of capsules, and are called “caplets”.

Constituents of Tablet

A typical tablet mainly contains one or more active ingredients, diluents, disintegrating agents, binder, lubricating agent, glidant, antiadherent, and small amount of coloring and flavouring agent(if needed).

Pie chart of constituents of Tablet

Types of Tablet

Tablets are broadly classified into two groups namely:

1)      Compressed tablet

2)      Molded tablet.

Compressed Tablet

Compressed tablets are formed by compression. There are various types of compressed tablets, such as

• Uncoated  tablets
• Coated tablets

* Sugar –coated tablets

* Film-coated tablets

* Enteric-coated tablets

 * Press-coated tablets

• Multiple compressed tablets
• Controlled –release tablets
• Effervescent tablets
• Tablets for solution
• Buccal & sublingual tablets
• Immediate release
• Delayed release
• Chewable tablets
• Lozenges
• Soluble tablets

Molded Tablet (Tablet Triturates,TT)

Molded tablets are made from moist materials, using a triturate mold. Two types of molded tablets –

• Dispersing  tablets
• Hypodermic tablets

Essential qualities of a good tablet

• Accurate & uniform weight
• The drug should be uniformly distributed throughout the tablet
• Absence of incompatibilities
• The tablet should not be too hard to disintegrate
• Stability & hardness
• Pleasing appearance
• Ease of manufacture
• Economy of production

Advantages of tablets

• Tablets are easy to carry
• They are easy to swallow
• Unpleasant odor and taste can be masked by film and suger coating.
• Provide prolong stability compared to the other dosage form
• Production costs are relatively low
• Self administration is possible
• Absence of alcohol

Disadvantages of tablet

• Not suitable for children
• Takes long time for absorption
• Patients with vomiting & diarrhea cannot take
• First pass metabolism occur

Excipients used in Tablet manufacturing

Excipients are pharmacologically inert substances which used in addition to the active ingredients for compounding of tablets in order to confirm desirable characteristics of the final products. Excipients that are used in the tablet formulation are

 Diluents:

Diluents may be defined as inert substances which are added to tablet formulation to increase bulk of the individual tablet in order to make the tablet a practical size for compression when the drug dose itself is inadequate for the required bulk. As for example lactose, maize starch, avicel, ludipress etc.

 Binders:

Binders are inert adhesive materials which are used to imparts cohesive qualities to the powder material and bind them together for compression. As for example solution of povidon k-30, HPMC solution, maize starch paste etc.

 Disintegrants:

 Disintegrants are agents that are added to the tablet formulation to facilitate breakdown or disintegration of the tablet when it contracts with water or fluid inside the body. As for example sodium starch glycolate, cross povidone, sodium CMC, etc.

Lubricants:

Lubricants are agents used in tablet formulations to reduce friction during tablet compression for the ejection of the tablets from the die. As for example magnesium stearate, calcium stearate, stearic acid, etc.

Anti-adherents:

Agents that prevent sticking of any of the tablet granules to the face of the punch and the die wall. As for example purified talc, etc.

Glidants:

Agents that improve flow properties of the granules or powder by reducing friction. As for example Aerosil-200, etc.

Colorants:

Agents that are used to impart color to the tablet. As for example FD&C Blue-1, FD&C Green-3, etc.

Flavouring Agents:

Agents that help to make the tablet taste better. As for example menthol, vanillin, cocoa butter, etc.

Production steps of Tablets

Production area of tablets are divided into various region as

1. Raw materials
2. Warehouse
3. Dispensing
4. Processing

  Granulation

  Blending

  Compression

  Tablet coating( if needed)

1. In process control
2. Packaging
3. Finished products
4. Warehouse for Distribution.

 Dispensing Unit

From the warehouse at first all the raw materials are bought into the dispensing room where the required amount of material is weighted.  Dispensing is the first step of manufacturing. Dispensing of raw material is done in the dispensing boot under laminar airflow. At first all excipients are dispensed and then the active ingredients are dispensed. Raw materials must be approved From QC department before dispensing. After dispensing and before manufacturing all the raw materials are kept in the dispensing bulk room and all necessary data are recorded.

Process of dispensing

1. Requisition is given to warehouse for raw materials prior to granulation
2. Raw materials are collected from warehouse and transferred to a clean dispensing room.
3. Dispensing condition should be maintained
4. Weighing of raw materials should be according to MO (manufacturing order)
5. Checking of quantity dispensed
6. Excess material returned to warehouse.

Steps of Production

Granulation Area

Granulation is the process in which the powder particles of raw materials are made to form larger particles in order to facilitate compression for the production of tablet. All the materials are received from the dispensing unit and granulation is performed. For suitable granulation, it is required to have 30-40% powder and 60-70% granules and also 1-5% moisture in compressing particles.

Most powders cannot be compressed directly into tablets because-

  The lack the proper characteristics of binding or bonding together into a compact entity.

  They do not ordinarily possess the lubricating and disintegrating properties required for    tableting.

Why Granulation is needed?

1. To prevent segregation of the constituents in the powder mix
2. To improve flow properties of the mix
3. To improve compression characteristic of the mix
4. The granulation of toxic materials will reduce dust generation
5. Granules are denser and thus occupy less volume per unit weight.

Types of Granulation

1. Wet Granulation
2. Dry Granulation

Wet Granulation

Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis.

This is the most widely used and most general method of tablet preparation. Its popularity is due to the greater probability that the granulation will meet all physical requirements for the compression of both tablets.

 Flow Chart of Wet Granulation

Advantage of Wet granulation

      Improve flow properties

      Densification

      Improved compression characteristics

      Reduction in dust

      Prevention of segregation of powder mix

Disadvantage of Wet granulation

      Stability may be a concern for moisture sensitive drug

      Time, space and equipment required are costly

Problems associated with Wet Granulation

During wet granulation some problems are found Such as  :

1)      Doughy mass

2)      Screen clogging

3)      Moisture sensitivity

Descriptions of them are given below:

Doughy Mass:

 It is a common tableting problem during wet granulation.

Reasons /causes:

• Too much water
• Over mixing
• Wrong binder

 Remedy:

• Add granulation water slowly.
• Reduce water or mixing time.
• Appropriate binder is used
• Use alcohol/water or alcohol as granulating fluid –select.

Screen Clogging:

When too much water is used in mass then screen clogging occur.

Reasons /causes:

• Too much water in mass
• Doughy or sticky wet mass
• Mass sensitive to water content
• Gummy binder
• Component or active ingredient

Remedy:

• Avoid oscillating granulator and use extrusion type granulator or fitz mill.
• Reduce mixing time
• Incorporate ingredient less sensitive to water.
• Use appropriate binder.

Moisture sensitivity:

Reasons /causes:

• Instability with water

Remedy:

• Use ethyl or isopropyl alcohol as granulating fluids ,ethyl cellulose ,PVP as binder .
• Slugging or dry granulation method.

Dry granulation

Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation.

Advantage of dry granulation

      One step process

      Time saving

      Moisture sensitive drugs can be granulated

Disadvantage of dry granulation

      Decreased compression characteristics

      Excess dusting

Condition for manufacturing of Granules

• Relative Humidity: Not more than 55%.
• Temperature: Below 25⁰C.

Problems associated with Dry Granulation

During dry blending some problems are arise. They are:

1)      Particle agglomeration

2)      Non Uniformity of mix

3)      Segregation

Particle Agglomeration:

During dry blending some particles are gathered together into larger aggregates.

Reasons /causes:

Occurs with fine cohesive powder which causes “balling up” and poor distribution.

Remedy:

• Fine screen cohesive compound into bulk mix
• Use a more effective mixer with shearing action
• Blend the Cohesive powder with a portion (5_10)% of the excipients in an efficient mixer ,add the bulk and blend normally

 Non –Uniformity of Mix:

 Sometimes mixing is not properly done and problems are arise:

Reasons /causes:

•  Improper blender load
• Insufficient mixing
• Over blending

Remedy:

• Use recommended powder load in blender
•  Increase mixing time

Segregation:

Sometimes dry blending particles are segregate.

Reasons /causes:

• Particle size distribution too wide .
• Over blending

Remedy:

• Narrow particle size range of components
• Reduce blending time and establish optimum mixing condition.

Steps involved in Dry Granulation

Flow Chart of Steps of Dry Granulation

Mixing and Blending

A powder blend should be as uniform as possible to assure the proper amount of medication in each dosages unit. The blending of solid particles is affected by the shape, density, size and size range of the particles, and surface effects such as absorbed liquid film, electrostatic charges and Van dar Waals forces. Small particles are difficult to blend because they exhibit poor fluidity. However, more important than actual particle size is particle size range. All drugs and chemicals should be reduced to approximately the same size prior to weighing and mixing.

Machinery Used in ARISTOPHARMA LTD.:

Mixing Machine for Dry and Wet Mixing 

1. Planetary Mixer

Company Name: Gansons, India

Capacity           : 60-80kgRPM

RPM                 : 45 (if rotate fast), 30 (if rotate slow)

1. Rapid Mixer Granulator (RMG)

Company Name: Saral Engineering

Capacity            : 160kg

RPM (Propeller): 300 (fast), 120 (slow)

1. Pa+m Glatt auto processor or Fluid bed processor

Country             : India (Germen Technology)

Capacity            : 500L

 Spray rate          : 70 (RPM)

               Machine used for Drying

1. Fluid bed dryer fg 120

Company Name: JIAFA, China

Capacity            : 120kg

1. Myth Fluid bed dryer

Company Name: Myth, Bangladesh.

Capacity            : 70kg

Machine used for Blending

1. Double cone blender

Company Name: Myth, Bangladesh

Capacity            : 300kg

RPM                  : 20-22

1. IBC blender HTD 800

Company Name: JIAFA, China

Capacity            : 400L

RPM                  : 1-15

1. Y-cone blender
2. Drum blender

Machine used for Crushing

1. Multimill

Main parts of Machine

Planetary mixer:

1. Planetary mixer vat
2. Planetary baffle
3. Solution input device

Rapid Mixing Granulator:

1. Rapid mixer vat
2. Blade
3. Chopper
4. Solution input channel
5. Mixer output device

Fluid Bed Dryer:

1. Heating device
2. Retarding chamber
3. Lifting device
4. Damping zone
5. Ring filter bag
6. Shaker
7. Fluid bed vat

Multimill:

1. Hopper
2. Holder and pin
3. Blade
4. Screen
5. Screen holder
6. Collector funnel

Double Cone Blender:

1. Lid
2. Product output channel
3. Body

Y-Cone Blender:

1. Lid
2. Body

Compression

Compression is the process of applying pressure to a material. In pharmaceutical tabletting an appropriate volume of granules in a die cavity is compressed between an upper and lower punch to consolidate the material into a single solid matrix which is subsequently ejected from the die cavity as an intact tablet.

Flow chart of tablet compression

 Production of Tablet by Direct Compression Method

Flow chart of Direct Compression Method

Machinery Used for Tablet Compression

Three types of compression machine is used in ARISTOPHARMA LTD. These are

1. D-tooling compression machine
2. B-tooling compression machine
3. D-B tooling compression machine

D-tooling compression machine

Number of station: 16, 27, 30, 37.

Maximum tablet diameter: 23mm

Maximum depth of fill: 20.5mm

Diameter of die: 38.1mm

Length of die: 23.81mm

Diameter of punch: 25.4mm

Length of upper punch: 133.65mm

Length of lower punch: 133.65mm

B-tooling compression machine

Number of station: 35, 45

Maximum tablet diameter: 16mm

Maximum depth of fill: 17mm

Diameter of die: 30.16mm

Length of die: 22.22mm

Diameter of punch: 19.05mm

Length of upper punch: 133.65mm

Length of lower punch: 133.65mm

D-B tooling compression machine

Number of station: 23

Machine Name and Description used by ARISTOPHARMA LTD.

Machine name: CPD-37

Company name: Cadmach, India

Category: D-tooling, 2 channel

Number of station: 37.

Machine name: MRC-30N

Company name: Sejong, South Korea.

Category: D-tooling, single channel, PLC

Number of station: 30.

Machine name: MRC-45D

Company name: Sejong, South Korea.

Category: B-tooling, 2 channel, PLC

Number of station: 45

Machine name: CMB-35 (2pcs)

Company name: Cadmach, India

Category: B-tooling, 2 channel

Number of station: 35.

Machine name: CMD-3B-27

Company name: Cadmach, India

Category: D-tooling, 2 channel

Number of station: 27.

Machine name: CMD-CB-23

Company name: Cadmach, India

Category: D-B tooling, single channel

Number of station: 23.

Machine name: PTK-52

Company name: Sejong, South Korea

Category: B-tooling, 3 layer, single channel

Number of station: 52.

Sejong Compression Machine

Sejong is a South Korean company and t5his machine is also called programmable logic control (PLC) machine. It is fully automatic machine. Machine Unit has the capacity to deliver 54,000 to 216,000 tablets per hour.

Main parts of Sejong compression machine:

1. Hopper
2. Feed frame
3. Feeder stands
4. Channel
5. Force feeder
6. Upper and Lower turret
7. Upper punch safety guard
8. Safety cover
9. Cam (according to product)
10. Roller (upper and lower)

Problem during tablet compression

1.     Capping & Lamination

Cause:

      Use of too dry granules in compression

      If compression pressure is too high

Remedy:

      By altering the pressure adjustment

      By using proper granules and required amount of fine particles

 2.     Picking and sticking

Cause:

      For using wet granulation during compression

      Excessive moisture content of the granules.

 Remedy

      By using dry granules and by adding a lubricant to the granules

      By replacing the worn dies and punches.

 3.     Hardness variation

Cause:

      Space between upper & lower punches at the time of compression

      Inappropriate pressure applied in the upper punches

Remedy

      The defect can be overcome by solving the causative effects.

Coating of Tablets

Coating is the process in which a core material is coated in order to provide a means of protecting the drug substance (API) from the environment particularly light and moisture. The application of coating of tablets which is an additional step in the manufacturing process increases the cost of the product. Again the coat must be dissolved before disintegration and dissolution of the tablet. Temperature and humidity must be controlled during coating process. Therefore, the reason to coat a tablet is usually based on one or more of the following objectives…..

Reasons for coating:

• Improving product stability
• To increase the elegance of the product
• To mask unpleasant test
• To save the drug from the attack of gastric HCL acid.
• To get delayed action from the product
• To save the drug from moisture

Types of coating

1.     Sugar coating

Purpose of sugar coating

      Protection from sun, moisture and environment

      To mask bitter taste & odor to increase the aesthetic value

      Prevent dusting

 2.     Film coating

Purpose of film coating

      Masking of taste, odor and appearance

      Can act as a barrier over the surface of the tablet

      Enteric coating

      Can modify the release of the drug

 3.     Enteric coating

      Purpose of Enteric coating

      Modification of drug release

      Repeat action and give sustained release pattern

      Stop gastric irritation

Coating types depend upon

      Tablet surface

      Tablet shape

      Nature of active

Flow chart of types of coating

Preparation of coating solution and process of coating

Coating agent+Solvent                   Mixing the solution properly by propeller                    Coating solution

 Setting the inlet and outlet temperature, pan speed air pressure

And distance of gun to tablet bed

Charging tablets in the coating solution by the nozzle

Spraying the coating solution by the nozzle

Turning off the exhaust fan and blower

Spraying of the polishing agent

Turning on the exhaust fan

Rolling the tablets

Cooling the tablet

Coated tablet

Flow chart of Coating process

Ingredient used in Coating

Sugar coating: In sugar coating sucrose paste is use. Sucrose is dissolve in purified water to produce sucrose paste. Gum acacia, Gelatin paste also used in sugar coating.

Film coating: In film coating; HPMC, Eudragit L-100 and L-50 are widely used.

Enteric coating: In enteric coating cellulose acetate phthalate, Shellac, etc polymer is used.

Room condition during coating

Relative Humidity: Not more than 50%

Temperature: Below 25°C

Problems associated with Coating

Logo bridging

Cause:

• Surface characteristics of the product being coated
• Inadequate adhesion of film coating
• Inadequate design of logo (e.g. too detail/fine

Remedy:        

• Modify core formulation to include more hydrophilic ingredients
• Increase core porosity
• 0Using formulation with increased adhesion property.
• Increase area within the deposing and modified angles.

Core erosion

Cause:

• Inherent softness or high friability of core.
• Excessive pan speed in coating process.
• Spray rate too low.
• High sensitivity of core to moisture as coating is applied.

 Remedy:

• Increase mechanical strength of core.
• Decrease pan speed.
• Increase spray rate.

Edge chipping/erosion

Cause:

• Low mechanical strength of coating
• Excessive pan speed
• Low solid content in coating liquid
• Low spray rate
• Sharp edges on tablets
• Worn tablet punches

Remedy:

• Using formulation with increased mechanical strength
• Decreased pan speed
• Increase solid content in coating liquid
• Decrease spray rate
• Use modified punch design

Picking/sticking

Cause:

• Spray rate too high
• Inadequate drying condition
• Pan speed too low
• Inadequate atomization of coating liquid
• Poor distribution of coating liquid

Remedy:

• Decrease spray rate
• Increase drying condition
• Increase pan speed
• Increase atomizing air pressure/volume
• Increase number of spray gun

Cracking

Cause:

• Low mechanical strength of coating, exacerbated by inadequate plasticization, excessive pigmentation.
• Core has significantly different thermal expansion characteristics than coating.
• Extended strain relaxation of core after compaction.

Remedy:

• Selecting formulation with increased mechanical strength and elasticity properties.
• Avoid use of mineral type fillers (e.g. CaCO₃, CaSO₄, MgCO₃ etc.)
• Extend holding period of tablets prior to submitting them to coating process.

Peeling

Cause:

• Low mechanical strength of coating
• Poor adhesion of coating to tablet surface

Remedy:

• Using ingredients of improved mechanical strength.
• Using ingredients with improved adhesion properties.

Orange peel/roughness

Cause:

• Viscosity of coating liquid is too high
• Poor atomization of coating liquid
• Excessive drying condition
• Over wetting (causing coating too rub)

 Remedy:

• Decrease solid content of coating liquid
• Increase atomizing air pressure/volume
• Decrease inlet air temperature/flow rate
• Decrease spray rate

Twinning

Cause:

• Spray rate too high
• Pan speed too low
• Inappropriate tablet shape

Remedy:

• Decrease spray rate
• Increase atomizing efficiency
• Increase pan speed
• Select new tablet shape that decrease chances of flat surfaces coming into contact during application of coating liquid. (e.g. avoid capsule shape tablet with thick side wall)

Tablet-to-tablet color variation (Mottling)

Cause:

• Too little coating applied
• Inadequate mixing of tablet during coating
• Poor opacity (or hiding power)
• Solid content of coating liquid too high
• Insufficient number of spray gun

Remedy:

• Increase quantity of coating applied
• Increase pan speed/increase improve baffle system
• Reformulate coating with respect to colored ingredients or use an opacified white pre-coat.
• Decrease solid contents of coating liquid.
• Increase number of spray gun.

Machinery Used for Coating at ARISTOPHARMA LTD.

Machine name: PA+M Glatt

Country: India

Capacity: 500kg

Number of Nozzle: 5

Spray pressure: 2bar

Machine name: NR-COTA (FC)

Country: Thailand

Capacity: 90-110kg

Machine name: NR-COTA 2 TC

Country: Thailand

Capacity: 200kg

Machine name: Sugar coating Pan

Country: India

Capacity: 70k

Capsule is a solid dosage form; in which medicine are enclosed in hard or soft capsule shell, made from gelatin. ARISTOPHARMA LTD only uses hard gelatin capsule shell for production.

The contents of capsules may be solid, liquid or of a paste-like consistency. They consist of one or more active substances with or without excipients such as solvents, diluents, lubricants and disintegrating agents. The contents do not cause deterioration of the shell. The shell, however, is attacked by the digestive fluids and the contents are released.

Classification of Capsules

There are various types of capsule

  Hard gelatin capsules

  Soft gelatin capsules

  Gastro-resistant capsules

  Modified release capsules

The active is filled in the empty the hard gelatin capsule shell in the form of-

  Powder

  Pellets

Shell size of capsules

ARISTOPHARMA LTD uses 6 different sizes of capsule shell. These are

   Shell size 00

  Shell size 0

  Shell size 1

  Shell size 2

  Shell size 3

  Shell size 4

Encapsulation of Capsules

 Steps of Encapsulation

1. Sieving of raw material (active & excipients)
2. Mixing (Double cone blender)
3. Compaction (If required) if bulk material is micronized or normal grain
4. Encapsulation
5. Polishing
6. Blister/ foil pack

Process of Encapsulation

1. Empty shell are taken in empty shell hopper
2. Empty shells are transferred from hopper to die holder
3. Body and cap are separated by vacuum pump
4. Pellets/ ingredients are incorporated into the body
5. Sealer seal the body and cap
6. Ejection

Pellets

Pellets are the dosage form mostly defined as the circular granule like beads where the drug is coated on to the surface of the NPS (Non-peril-seeds) made using sugar, lactose and maize starch.

Filling of the capsule shell

First, the weighed amount of active ingredients and additives filling operation. Now the empty capsule shell are taken to separate them into cap and body. The body is taken filled with the prepared powder mixer or granules. Now the cap is pressed in the body to close it. Finally the filled capsule shells are ejected for cleaning and polishing.

Weight of raw materials

 Sieving of all raw materials

All Ingredients blending (Drum mixing)

Flow chart of filling of capsule shell

Polishing of Capsules

Polishing of capsule is done by

      Polishing by Hand

      Polishing by Machine

Advantages of Capsule

  Neat and elegant in appearance

  Tasteless and odorless means of drug administration

  Rapid release of drugs

Disadvantages of Capsules

  Capsule is not suitable for liquids.

  Very soluble drugs should not be dispensed in capsules.

  Rapid release of drugs may cause gastric irritation.

Machinery used in ARISTOPHARMA LTD for capsule filling

Machine name: Semi automatic capsule filling machine

Manufacturer: P+am Pharmaceuticals

Country: India

Capacity: 15000-17000 per hour

Machine name: Automatic capsule filling machine

Manufacturer: Hanli, Korea

Capacity: 30000 per hour

Machine name: Automatic capsule filling machine

Manufacturer: Sejong, Korea

Capacity: 90000 per hour

Machine name: Hand filling machine

Manufacturer: Pharmachem, India

Capacity: 8000 per hour

Machine name: Capsule polishing machine

Manufacturer: P+am pharmaceutical, India

Manufacturing of Powder for Suspension

By Direct Mixing method ARTSTOPHARMA LTD produces Powder for suspension.

Flow chart for Direct Mixing for the manufacturing of Dry Syrup

Crushing the sucrose in FITZ mill at 3000 rpm

Transfer of half portion of sucrose from step-1 into

a double cone blender by passing through a 20 mesh screen

Transfer of all other excipients in the blender to blend for 30 minute

Transfer the mix from the double cone blender by

Passing through a 20 mash screen

Machinery used in the Dry Syrup Manufacturing unit

1. Double cone Blender
2. Dust collector
3. FITZ mill
4. Bottle filling machine
5. Bottle sealing machine

Condition for manufacturing Dry Syrup

        Relative Humidity: Not more than 45%.

        Temperature: Below 25⁰

Area for Cephalosporin Manufacturing

According to cGMP regulations separate facility for cephalosporin is required to prevent cross contamination with other penicillin products or non beta-lactum products. Unintended exposure with Cephalosporin products may cause health concern to patients sensitive to Cephalosporin.

• Fully separated, well established and isolated manufacturing area only for Cephalosporin.
• Highly sophisticated HVAC system and AHU are used to condition, monitor and supply clean air to the working zone.
• Production floors and wall are covered with epoxy resin.
• A complete set up of machineries required for tablets and capsule productions is established only for Cephalosporin’s.
• More precautions are maintained in each and every step during production, filling, Sealing and packaging to prevent cross contamination.
• Officers and the workers are trained specially to work more carefully in order to minimize cross contaminations.
• Well furnished change rooms are maintained each floor of the production areas.
• Samples during various steps of manufacturing are collected by QC officers all the times for proper manufacturing.

Some are parts:

Plant Training on Aristopharma Ltd (Part 1)

Plant Training on Aristopharma Ltd (Part 2)